Modest CaV1.342-selective inhibition by compound 8 is β-subunit dependent

Two voltage-gated calcium channel subtypes-Ca(V)1.2 and Ca(V)1.3-underlie the major L-type Ca2+ currents in the mammalian central nervous system. Owing to their high sequence homology, the two channel subtypes share similar pharmacological properties, and at high doses classic calcium channel blockers, such as dihydropyridines, phenylalkylamines and benzothiazepines, do not discriminate between the two channel subtypes. Recent progress in treating Parkinson's disease (PD) was marked by the discovery of synthetic compound 8, which was reported to be a highly selective inhibitor of the Ca(V)1.3 L-type calcium channels (LTCC). However, despite a previously reported IC50 of similar to 24 mu M, in our hands inhibition of the full-length Ca(V)1.342 by compound 8 at 50 mM reaches a maximum of 45%. Moreover, we find that the selectivity of compound 8 towards Ca(V)1.3 relative to Ca(V)1.2(B15) channels is greatly influenced by the beta-subunit type and its splice isoform variants.